Aggressive systolic blood pressure control in older subjects: benefits and risks

Systolic hypertension, especially isolated systolic hypertension (ISH) is very common in older subjects aged ≥ 65 years and is a major risk factor for cardiovascular disease (CVD), strokes, heart failure (HF) and chronic kidney disease (CKD). It is also, directly and linearly related with these complications irrespective of sex, or ethnicity, but it is worse with the advancement of age. Effective control of systolic blood pressure (SBP), is associated with significant reduction in the incidence of these complications. Currently, there is a debate about the optimal SBP control in view of the Systolic Blood Pressure Intervention Trial (SPRINT) showing beneficial cardiovascular (CV) effects of intensive SBP of < 120 mmHg in older patients. Also, the recently released blood pressure (BP) guidelines by the American College of Cardiology, the American Heart Association and the American Society of Hypertension (ACC/AHA/ASH) recommend a SBP reduction of < 130 mmHg. These SBP treatment recommendations are in contrast with the current (JNC VIII) committee of BP treatment guidelines, which recommend a SBP reduction < 150 mmHg for the same age of patients. All these different recommendations have created a debate regarding the optimal treatment targets for the systolic hypertension of the elderly patients. To gain more information a focused Medline search was conducted from 2010 to 2017 using the terms, systolic blood pressure, aggressive control, older subjects, treatment guidelines, and 37 pertinent papers were retrieved. The findings from these studies suggest a SBP reduction of < 140 mm Hg for persons aged ≥ 60 years, with an attempt for SBP reduction to ≤130 mm Hg in healthier subjects and hose with CVD, DM, and CKD. Care should be taken not to further reduce the SBP in older subjects if their DBP is ≤60 mmHg for the fear of J-curve effect.     

抗结核药物作用新靶点及其研究进展

结核病是威胁我国乃至全世界的健康问题。由于细菌变异、治疗方案不合理和药物滥用等原因导致细菌耐药情况越来越严重,耐药结核病已经威胁到了全人类的健康安全。近10年来针对结核分枝杆菌各种新靶点的抗结核新药已经陆续进入临床试验,作者对抗结核分枝杆菌研究中细胞壁合成、蛋白质合成和能量代谢机制的新靶点进行梳理和分析,并且对一些相关的新型化合物进行简要介绍,以期为抗结核药物的研发提供参考。     

A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia‐inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Testing and improving experimental parameters for the use of low molecular weight targets in array-CGH experiments

Array-comparative genomic hybridization (CGH) has evolved as a useful technique for the detection and characterization of deletions, and, to a lesser extent, of duplications. The resolution of the technique is dictated by the genomic distance between targets spotted on the microarray, and by the targets' sizes. The use of region-specific, high-resolution microarrays is a specific goal when studying regions that are prone to rearrangements, such as those involved in deletion syndromes. The aim of the present study was to evaluate the best experimental conditions to be used for array-CGH analysis using low molecular weight (LMW) targets. The parameters tested were: the target concentration, the way LMW targets are prepared (either as linearized plasmids or as purified PCR products), and the way the targets are attached to the array-CGH slide (in a random fashion on amino-silane coated slides, or by one amino-modified end on epoxysilane-coated slides). As a test case, we constructed a microarray harboring LMW targets located in the CREBBP gene, mutations of which cause the Rubinstein-Taybi syndrome (RTS). From 10 to 15% of RTS patients have a CREBBP deletion. We showed that aminosilane- and epoxysilane-coated slides were equally efficient with targets above 1,000 bp in size. On the other hand, with the smallest targets, especially those below 500 bp, epoxysilane-coated slides were superior to aminosilane-coated slides, which did not allow deletion detection. Use of the high resolution array allowed us to map intragenic breakpoints with precision and to identify a very small deletion and a duplication that were not detected by the currently available techniques for finding CREBBP deletions.     

The emerging role of Notch pathway in ageing: Focus on the related mechanisms in age-related diseases

Notch signaling is an evolutionarily conserved pathway, which is fundamental for the development of all tissues, organs and systems of human body. Recently, a considerable and still growing number of studies have highlighted the contribution of Notch signaling in various pathological processes of the adult life, such as age-related diseases. In particular, the Notch pathway has emerged as major player in the maintenance of tissue specific homeostasis, through the control of proliferation, migration, phenotypes and functions of tissue cells, as well as in the cross-talk between inflammatory cells and the innate immune system, and in onset of inflammatory age-related diseases. However, until now there is a confounding evidence about the related mechanisms. Here, we discuss mechanisms through which Notch signaling acts in a very complex network of pathways, where it seems to have the crucial role of hub. Thus, we stress the possibility to use Notch pathway, the related molecules and pathways constituting this network, both as innovative (predictive, diagnostic and prognostic) biomarkers and targets for personalised treatments for age-related diseases.     

溶血磷脂酸在卵巢癌进展中的机制研究

在卵巢癌的发生发展中,脂代谢发挥重要作用,溶血磷脂酸(LPA)作为一种生物活性磷脂分子,通过与多种G蛋白偶联受体结合,参与卵巢癌的增殖、转移和侵袭活动。一方面,LPA可通过促进肿瘤血管新生、调节细胞周期、抑制凋亡、促进糖代谢及维持肿瘤干细胞(CSC)的特性来促进卵巢癌细胞增殖;另一方面,LPA可增加基质金属蛋白酶(MMP)及尿激酶型纤溶酶原激活物(u PA)的表达、干预细胞间连接和骨架蛋白、促进上皮-间质转化(EMT),进而促进卵巢癌的转移和侵袭。此外,卵巢癌患者血浆中高水平的LPA单独或与卵巢癌的其他肿瘤标记物联合检测具有更高的敏感度和特异度。综述LPA在卵巢癌增殖、转移和侵袭中的作用机制以及潜在的诊断、治疗靶点方面的研究进展。     

抗视网膜脉络膜新生血管性疾病治疗药物靶点的研究进展

新生血管性年龄相关性黄斑变性(nAMD)、糖尿病视网膜病变(DR)等眼底病继发形成新生血管,是致盲的重要原因之一.抗血管内皮生长因子(VEGF)治疗是当前主流疗法.但仍存在部分患者对其疗效欠佳等局限,临床仍需要开发新的药物靶点.     

Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis

 Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic autoimmune-mediated diseases of the biliary tree, resulting in a loss of bile ducts. There are morphological features that clearly distinguish them from each other: in PBC, there is overt destruction of the bile ducts with disruption of the basement membrane; in PSC there is abundant periductular fibrosis with shrinkage and subsequent loss of the bile ducts. In order to see if the disparate histopathology is paralleled by different immunohistology we looked at a panel of epitopes on bile duct epithelia especially to see if biliary epithelial cells may present as targets for cell mediated immune respone. In PBC bile duct epithelial cells mostly expressed CD58 (lymphocyte function-associated antigen 3), CD80 (B7 BB1), and CD95 (Fas). In PSC, however, these epitopes were only expressed in a few examples to a lower degree. The respective effector T lymphocytes were positive for CD2 and CD28. Subtyping of the lymphocytes in the liver tissue further showed a predominance of CD4 positive T cells over CD8 cells up to 2-to-1 in both diseases. Determination of lymphocytes by cytokines to Th1 or Th2 subtype showed a majority of Th1 lymphocytes in PBC and PSC. We conclude that in PBC bile duct epithelial cells may display features of target cells of a T cell-mediated immune reaction with the Th1 cells predominating. In PSC other mechanisms of bile duct loss may play a role, since in this disease the majority of cells lack essential epitopes that constitute targets of cell mediated immunity. Received: 19 November 1996 / Accepted: 26 February 1997     

骨合成促进剂治疗骨质疏松症的优势*

背景：骨质疏松引发的骨折及其并发症严重影响老年人及绝经妇女生活质量。 目的：旨在探究主要骨合成促进剂的研究新进展,以促进其临床应用。 方法：由第一作者应用计算机检索PubMed、中国期刊全文数据库(CNKI)、维普数据库和万方数据库1997年1月至2012年8月相关文献。在标题、摘要、关键词中以“bone formation,osteoporosis,osteoblast,osteoclast,bone metabolism,PTH,Wnt signaling,medicine,target,inhibitor”或“骨合成,骨质疏松,成骨细胞,破骨细胞,骨代谢,甲状旁腺激素,Wnt信号,药物,靶目标,抑制剂”为检索词进行检索。初检得到398篇文献,最终选择40篇文献进行综述。 结果与结论：骨合成促进剂不同于传统单纯抗骨吸收骨质疏松药物,能进一步增加骨量,对骨折风险的降低亦有一定作用。骨合成促进剂治疗骨质疏松有重要的临床价值。甲状旁腺激素及甲状旁腺激素相关肽,Wnt信号通路相关分泌型糖蛋白分子抑制剂如抗硬化蛋白(Selerostin)抗体、Dkk1抑制剂、sFRP抑制剂、GSK3β抑制剂等是骨质疏松相关骨合成促进剂中的研究热点,但临床应用于同样存在一些局限性。